Project Summary/Abstract The candidate, Gustavo E. Velasquez, MD, MPH, is an infectious disease physician at Brigham and Women?s Hospital and an instructor at Harvard Medical School. This K08 career development award will prepare the candidate for an independent investigative career in tuberculosis clinical trials research. Dr. Velasquez?s career goal is to establish himself as a clinical trialist with specific expertise in the evaluation of drug toxicity in complex multidrug regimens for the treatment of tuberculosis. Dr. Velasquez proposes a five-year program during which he will conduct clinical research that enhances our understanding of the safety and tolerability of new and repurposed drugs to treat multidrug-resistant tuberculosis (MDR-TB), using observational, experimental, and pharmacokinetic data. Dr. Velasquez will engage in an intensive mentored research experience with [1] Carole D. Mitnick, ScD, a tuberculosis epidemiologist and an international expert in tuberculosis clinical trials whose career has been dedicated to optimizing treatment for tuberculosis; [2] professor Helen M. McIlleron, MBChB, PhD, a clinical pharmacologist and an international expert in antituberculous and antiretroviral drug pharmacometrics; and [3] professor Daniel R. Kuritzkes, MD, an internationally recognized expert in HIV antiretroviral therapy. Two new drugs, bedaquiline and delamanid, and two repurposed drugs, clofazimine and linezolid, were recently recommended for MDR-TB treatment. A growing body of data is emerging from clinical trials of novel MDR-TB regimens using these drugs, yet high- quality evidence on their safety and tolerability?informed by pharmacokinetics?is sorely lacking. Dr. Velasquez will leverage his unique access to existing and forthcoming data from four clinical trials and two observational studies of tuberculosis patients to address this problem. He will [1] examine the safety and tolerability of bedaquiline and delamanid within conventional MDR-TB regimens; [2] estimate the effect of linezolid-dose reduction strategies on the safety and tolerability of MDR-TB treatment and the pharmacokinetics of linezolid; and [3] estimate the effect of plasma drug exposure on the safety and tolerability of combinations of new and repurposed drugs in a Phase III trial. His proposal strives to transform the evidence base for clinical decision-making around averting and managing toxicity during MDR-TB treatment. This project will apply novel methods to rich and rigorously collected datasets to develop an understanding of the relationship between combination regimens for MDR-TB, plasma concentration of the drugs, and treatment-emergent toxicity. The Division of Infectious Diseases at Brigham and Women?s Hospital and the Department of Global Health and Social Medicine at Harvard Medical School are an ideal setting to conduct the candidate?s proposed activities, due to the breadth and scope of multi-disciplinary collaborations in the control of tuberculosis and HIV that promote better health both in the United States and abroad.